1e3q

TORPEDO CALIFORNICA ACETYLCHOLINESTERASE COMPLEXED WITH BW284C51
See also AChE bivalent inhibitors (Part II).



Like other AChE bivalent inhibitors, BW284C51 (BW) interacts with TcAChE at both subsites of its active site - CAS and PAS. At the CAS, BW makes a cation-aromatic interaction via its quaternary group with Trp84 (colored orange), BW phenyl ring forms an aromatic-aromatic interaction with His440 and there is also an electrostatic interaction between the BW proximal quaternary group and Glu199. Near the PAS, BW interacts with Trp279 (colored cyan) via its distal quaternary group and forms an aromatic interaction with Tyr334. BW forms hydrogen bond with Tyr121 OH, and makes alkyl interactions with Phe331. The superposition of the complexed BW with two other AChE bivalent inhibitors DECA (decamethonium, colored gray, 1acl) and E2020 (Aricept, colored blueviolet, 1eve) reveals similar mode of binding. All these 3 inhibitors form cation-π and π-π interactions with active-site gorge aromatic residues (Tyr70, Trp84, Trp279 and Phe330 or Tyr334) (colored yellow). The superposition of DECA and E2020 shows their similar position at the active site. However, BW has a different trajectory. This causes different conformation of Phe330, which interacts more strongly with BW than with DECA or E2020. The conformations of other important residues at the active site are similar in all these inhibitor/TcAChE complexes. It has been shown experimentally that BW and E2020 bind to TcAChE approximately 100-fold more strongly than DECA. These findings could be explained by several reasons: i) E2020 and BW are less flexible than DECA; ii) the aromatic groups of E2020 and BW form favourable π-π interactions with TcAChE aromatic residues, in contrast to DECA; and iii) <scene name='1e3q/Shape/3'>BW and <scene name='1e3q/Shape/2'>E2020 aromatic groups occupy more volume and better fit the active-site gorge, than the <scene name='1e3q/Shape/4'>string-shaped DECA . Mutations of mouse or chicken AChE, corresponding to the TcAChE <scene name='1e3q/Active_site/10'>Tyr70, Trp84, Trp279 and Tyr121 <font color='red'>(colored red), cause significant increase of inhibition constant values for all these 3 inhibitors, supporting the notion that these residues are critical for inhibitor/AChE binding.

About this Structure
1E3Q is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
Structure of a complex of the potent and specific inhibitor BW284C51 with Torpedo californica acetylcholinesterase., Felder CE, Harel M, Silman I, Sussman JL, Acta Crystallogr D Biol Crystallogr. 2002 Oct;58(Pt 10 Pt 2):1765-71. Epub, 2002 Sep 28. PMID:12351819

Page seeded by OCA on Tue Jul 1 00:06:00 2008